GB2462611A

GB2462611A - Pharmaceutical composition comprising tetrabenazine

Info

Publication number: GB2462611A
Application number: GB0814695A
Authority: GB
Inventors: Andrew John Duffield
Original assignee: Biovail Laboratories International SRL; Cambridge Laboratories Ltd
Current assignee: Valeant Laboratories International Bermuda SRL
Priority date: 2008-08-12
Filing date: 2008-08-12
Publication date: 2010-02-17
Also published as: WO2010018408A3; US20140242063A1; US20100055133A1; GB0814695D0; WO2010018408A2

Abstract

A controlled release pharmaceutical composition in unit dosage form comprising tetrabenazine as the sole therapeutic agent and a release-retarding agent. The composition has a long half-life of some 13-15 hours. The release-retardig agent is a cellulose derivative such as hydroxypropylmethyl cellulose (HPMC) or hydroxypropyl cellulose (HPC).

Description

PHARMACEUTICAL COMPOSITIONS

This invention relates to pharmaceutical compositions containing tetrabenazine.

Background of the invention

Tetrabenazine (Chemical name: 1, 3, 4,6,7,1 lb-hexahydro-9, 1 0-dimethoxy-3 -(2-methylpropyl)-2H-benzo(a)quinolizin-2-one) has been in use as a pharmaceutical drug since the late 195 Os. Initially developed as an anti-psychotic, tetrabenazine is currently used in the symptomatic treatment of hyperkinetic movement disorders such as Huntington's disease, hemiballismus, senile chorea, tic, tardive dyskinesia, myoclonus, dystonia and Tourette's syndrome, see for example Ondo et at., Am. J. Psychiatry.

(1999) Aug; 156(8):1279-81 and Jankovic et at., Neurology (1997) Feb; 48(2):358-62.

The chemical structure of tetrabenazine is as shown in Figure 1 below.

CH3Oc1J Figure 1-Structure of tetrabenazine The compound has chiral centres at the 3 and 11 b carbon atoms and hence can, theoretically, exist in a total of four isomeric forms, as shown in Figure 2.

8 7 8 7 CH3O 6 CH3O 6 cH3ocHN: CH3O) 6 CH3O 6 cH3O1N4 CH3O14 Figure 2 -Possible tetrabenazine isomers Commercially available tetrabenazine is a racemic mixture of the RR and SS isomers.

Tetrabenazine has somewhat poor and variable bio availability. It is extensively metabolised by first-pass metabolism, and little or no unchanged tetrabenazine is typically detected in the urine. The major metabolite is dihydrotetrabenazine (chemical name: 2-hydroxy-3 -(2-methylpropyl)-1,3,4,6,7,11 b-hexahydro-9, 1 0-dimethoxy-benzo(a)quinolizine) which is formed by reduction of the 2-keto group in tetrabenazine, and is believed to be primarily responsible for the activity of the drug (see Mehvar et at., Drug Metab.Disp, 15, 250-255 (1987) andJ. Pharm. Sci., 76, No.6, 461-465 (1987)).

The preparation of tetrabenazine and of its salts, in particular the hydrochloride, is described in GB 789 789. The preparation of a-dihydrotetrabenazine and its salts, in particular the hydrochloride, is described in GB 800 969. The preparation of (�)-a-dihydrotetrabenazine is described by Brossi (Helv. Chim. Acta., 41:249-25 1 (1958)).

The preparation of (+)-a-dihydrotetrabenazine is described by Kilboum (Eur. J. Pharmacol, 278:249-25 1 (1995)). The preparation of 3,llb cis isomers of dihydrotetrabenazine is described in WO 2005/077946.

Tetrabenazine is an effective and safe drug for the treatment of a variety of hyperkinetic movement disorders and, in contrast to typical neuroleptics, has not been demonstrated to cause tardive dyskinesia. Nevertheless, tetrabenazine does exhibit a number of dose-related side effects including causing depression, parkinsonism, drowsiness, nervousness or anxiety, insomnia and, in rare cases, neuroleptic malignant syndrome.

Formulating drugs as controlled-release formulations can sometimes reduce the side effects of drugs by smoothing out the Cmax value and can also provide simplified once-a-day administration.

Tetrabenazine is soluble at acid pH (as found in the stomach) but the solubility decreases dramatically at the higher pH values found lower down the gastronintestinal (GI) tract. Comparative Example 1 as herein described illustrates that tetrabenazine is practically insoluble in the pH range of 3-12 and slightly soluble at pH 2 (as found in the stomach). Immediate-release formulation tablets comprising tetrabenazine which are currently available are designed to disintegrate in the stomach leading to dissolution and absorption of tetrabenazine in the stomach.

Immediate-release formulations require that a drug is administered in a high dose at a given time only to have to repeat that dose several hours or days later. This is inconvenient to the patient and can result in damaging side effects. In contrast, controlled-release formulations enable drugs to be delivered to the patient continually for prolonged time periods and in a controlled fashion.

However, the ambient pH increases moving down the GI tract. For example, the pH in the duodenum is about 6 and increases to about 7-8 in the ileum and decreases slightly in the colon to 5-7. At these pH levels tetrabenazine is practically insoluble.

Therefore, it would be expected that by formulating tetrabenazine as a controlled-release formulation, so preventing the drug from being released in the stomach and delaying release until the drug reaches regions of the GI tract where it is less soluble, the bioavailability of tetrabenazine would be significantly reduced.

Summary of the Invention

It has now been surprisingly found that tetrabenazine may be formulated as a controlled-release formulation to provide good bioavailability and a surprisingly long half-life (13-15 hours).

Accordingly, in a first aspect, the invention provides a controlled release pharmaceutical composition in a unit dosage form comprising tetrabenazine as the sole therapeutic agent and a release-retarding agent.

In a further aspect, the invention provides a pharmaceutical composition in the form of a tablet comprising tetrabenazine as the sole therapeutic agent in an amount of between 40-60 mg, and the composition further comprising lactose, starch, HPMC, talc and magnesium stearate.

In a further aspect, the invention provides a pharmaceutical composition for use in therapy.

In a further aspect, the invention provides a process for the preparation of a pharmaceutical composition, wherein the composition is prepared by mixing tetrabenazine and the release-retarding agent and optionally other excipients to form granules and compressing the granules to form a tablet.

The pharmaceutical composition may be in a solid dosage form selected from the group consisting of tablets, powders, capsules, sachets, troches and lozenges. Preferably, the solid dosage form is a tablet.

Where the composition is in the form of a tablet, the tetrabenazine is preferably dispersed in a matrix of release-retarding agent. The matrix can be formed by mixing the tetrabenazine and the release-retarding agent and optionally one or more other pharmaceutical excipients to form granules and then compressing the granules to form a tablet. Thus, in one embodiment, the composition can comprise granules compressed to form a tablet, wherein the granules comprise a mixture of tetrabenazine and the release-retarding agent and optionally one or more other pharmaceutical excipients.

Alternatively, the tablet may comprise a release-sustaining coating, which takes the form of a coating surrounding a tablet core.

Preferably, the unit dosage form of the controlled release pharmaceutical composition of the present invention comprises 10-110 mg of tetrabenazine as the sole therapeutic agent, more preferably 15-100 mg, or 20-90 mg, or 25-80 mg, or 30-70 mg, or 35-65 mg, or 40-60 mg of tetrabenazine as the sole therapeutic agent. Most preferably, the unit dosage form of the controlled release pharmaceutical composition of the present invention comprises 50 mg of tetrabenazine as the sole therapeutic agent. In another embodiment, the unit dosage form of the present invention comprises 25mg of tetrabenazine as the sole therapeutic agent. In another embodiment, the unit dosage form of the present invention comprises 75mg of tetrabenazine as the sole therapeutic agent. In another embodiment, the unit dosage form of the present invention comprises 100mg of tetrabenazine as the sole therapeutic agent.

Typically, tetrabenazine comprises 4-40% (w/w) of the composition, preferably 10- 30% (w/w), and preferably 15-25% (w/w). Most preferably, tetrabenazine comprises 20% (w/w) of the composition.

The release-retarding agent typically forms 10-50% (w/w) of the composition, more typically 20-40% (w/w), preferably 25-35% (w/w), for example approximately 30% (w/w).

The release-retarding agent of the present invention may be a cellulose derivative, such as hydroxypropylmethyl cellulose (HPMC) or hydroxypropyl cellulose (HPC).

Preferably, the cellulose derivative is HPMC. The HPMC may comprise different molecular weight distributions of the HPMC polymer, such as MethocelTM K4M (with a number average molecular weight of 82000), MethocelTM K100LV (with a number average molecular weight of 46000) and/or MethocelTM E15LV (Methocel E15LV Cellulose Ether (viscosity of 2 % solution in water = 12-18 cP (centipoise), which is equivalent to milipascal-seconds (mPa-s)), all of which can be obtained from the Dow Coming Chemical Company. Preferably, MethocelTM K100LV is used.

In one preferred embodiment, HPMC comprises 20-40% (w/w) of the composition of the present invention. Preferably, HPMC comprises 30% (w/w) of the composition.

The pharmaceutical composition may comprise one or more further pharmaceutical excipients including at least one of a diluent, disintegrant, glidant and lubricant.

Suitable diluents for use in the pharmaceutical composition of the present invention include microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol and talc, and mixtures thereof Preferably, the diluent is a sugar or sugar alcohol, and more preferably a sugar such as lactose. The diluent typically comprises 20-60% (w/w) of the composition, preferably 25-55% (w/w), more preferably 30-50% (w/w).

Solid pharmaceutical compositions of the present invention that are compacted into a dosage form, such as a tablet, may include the addition of a disintegrant to the composition. Disintegrants include croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glyco late and starch. Preferably, the disintegrant is starch. The disintegrant typically constitutes 5-25% (w/w) of the composition, and more typically 10-20%(w/w).

Glidants can be added to improve the flowability of a solid composition before compaction and to improve the accuracy of dosing especially during compaction and capsule filling. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc. Preferably, the glidant is talc and/or silicon dioxide. The glidant typically constitutes up to 3% (w/w) of the composition, more typically 0.5-2.5% (w/w), preferably 1-2% (w/w).

A lubricant can be added to the composition to reduce adhesion and/or ease the release of the product from the dye. Suitable lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. Preferably, the lubricant is magnesium stearate. The lubricant typically constitutes up to 2% (w/w) of the composition, more typically up to 1.5% (w/w), for example 0.2-1.5% (w/w), for example 0.4-0.8% (w/w).

Preferably, the diluent comprises 35-45% (w/w) of the composition, the disintegrant comprises 15-25% (w/w) of the composition, the glidant comprises 2-8% (w/w) of the composition and the lubricant comprises 1-2% (w/w) of the composition.

Other excipients that may be incorporated into the formulation include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry.

In a particularly preferred embodiment, the invention provides a controlled release tablet composition comprising: (i) 15-25% (w/w) tetrabenazine as the sole therapeutic agent; (ii) 25-30% (w/w) of HPMC as a release-retarding agent; (iii) 25-35% (w/w) of a solid diluent selected from sugars and sugar alcohols; (iv) 10-20% (w/w) of starch as a binder/disintegrant; and optionally (v) 0.5-3% (w/w) of a lubricant and/or glidant.

The tablet preferably comprises compressed granules wherein the granules contain a mixture of (i), (ii), (iii), (iv) and (v) above.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The most preferred route of administration of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.

The pharmaceutical composition of the present invention may be prepared in any dosage form such as a compressed granulate in the form of a tablet for example. Also, uncompressed granulates and powder mixes can be simply provided in a dosage form of a capsule or sachet. Therefore, dosage forms of the pharmaceutical composition of the present invention include solid dosage forms like tablets, powders, capsules, sachets, etc. The dosage form of the present invention may also be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

Capsules comprising either a hard or soft shell and containing the composition of the present invention may be prepared. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

A capsule filling of the present invention may comprise the granulates that were described with reference to tableting, a final blend of a granulate composition of the present invention mixed with one or more excipients, however they are not subjected to a final tableting step. Further, such capsules may be prepared by any of the methods well known in the pharmaceutical arts.

In a further embodiment, the present invention provides a pharmaceutical composition as described above for use in therapy, preferably for treating any disease or condition for which tetrabenazine is currently used.

The compositions may be administered once or twice daily, and more typically are administered once daily, or at any other frequency determined by a supervising physician.

The invention will now be illustrated, but not limited, by reference to the following

examples.

EXAMPLES

Example 1

250 mg tablets, dry granulation Table 1. Preferred tablet formulation of the present invention Ingredient Function 250 mg tablet (mg) Tetrabenazine Active agent 50 Lactose Diluent 78.9 Starch Binder/Disintegrant 40.5 HPMC (K4M) Controlled-release agent 75 HPMC (K100 LV) HPMC (E15LV) Talc Glidant 4 Magnesium stearate Lubricant 1.6 Tetrabenazine, lactose, starch and HPMC were sifted through a 30 mesh hand sieve into a suitable container. The powders were then mixed in a Hobart mixer for 10 minutes with the kneader forward on slow speed.

The talc was transferred through a 30 mesh hand sieve and into a suitable container and the magnesium stearate was transferred and sifted through a 60 mesh hand sieve into a

suitable container.

The sifted talc and magnesium stearate were added to the tetrabenazine, lactose, starch and HPMC in the Hobart mixer and all ingredients were mixed for 2 minutes with the kneader forward on slow speed to form the granulate.

The granulate blend was then sealed in polyethylene containers that have been double lined with polyethylene bags.

The 250 mg tablets were formed by compression using an 8 mm round, flat, bevelled edge punch with a single break line for both the upper and lower punches.

The compressed 250 mg tablets were packed into 85 ml HDPE bottles with inner polypropylene caps containing a liner consisting of Suryln / aluminium / polyethylene / bleached kraft membrane.

Example 2

The steady state pharmacokinetics of the 50 mg and 100 mg tetrabenazine controlled-release tablet formulation of the present invention were assessed.

In addition, the safety and tolerability of tetrabenazine administered as a controlled-release formulation was assessed.

The study included 9 healthy male and female volunteer subjects. Each subject received a daily dose of a 50 mg controlled-release tetrabenazine tablet for 7 days in Period 1 and a single dose of 2 x 50 mg controlled-release tetrabenazine tablets in Period 2. The subjects were resident in the clinic for 11 days during Period 1, and 5 days during Period 2. There was at least a seven day washout period between the last dose in Period 1 and the first dose of Period 2.

The concentration of tetrabenazine and its metabolites (ct-and 13-dihydrotetrabenazine (HTBZ)) was determined by taking blood samples from the subjects. In this regard, during Period 1 blood samples were drawn before each dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12 and 16 hours before the first dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours after the last (seventh) dose. During Period 2, blood samples were drawn before the single dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48 and 72 hours. After oral administration of the controlled-release tetrabenazine tablets, tetrabenazine was rapidly transformed into metabolites ct-HTBZ and f3-HTBZ with little parent compound detected in plasma (Figure 3). E15 E.

--t -HTSZ PEWOD 1, 1 -\ -8---Hmz, PEROD t 7 *--Te1rahnz. PERIOD 1.7 o

N

S 0 I

0 10 20 30 40 50 60 70 80 Tme{h) Figure 3 -Time profiles at steady state of mean plasma drug and metabolite concentrations at day 7 Steady state was achieved for both metabolites ct-HTBZ and f3-HTBZ at day 7 after a daily dose of 50 mg controlled-release tetrabenazine tablets for seven days. Peak plasma concentration at steady state was reached at 2 hours for ct-HTBZ (median Tmax) and at 1 hour (median Tmax) for f3-HTBZ. The elimination half-life, calculated from steady state plasma ct-HTBZ and f3-HTBZ concentration, was 13.53 hours for a-HTBZ and 12.48 hours for f3-HTBZ.

Dose accumulation was observed by comparing day 1 and day 7 Cmax and AUC data.

The a-HTBZ and f3-HTBZ absorption (Cmax and AUC) calculated from the blood samples collected before the last dose on day 7 was much higher than that on day 1.

In summary, both a daily dose of 50 mg tetrabenazine controlled-release tablets for seven days and a single dose of 2 x 50 mg controlled-release tetrabenazine tablet were well tolerated. After oral administration of controlled-release tetrabenazine tablets, tetrabenazine was rapidly transformed into ct-HTBZ and f3-HTBZ with little parent compound detected in the plasma. Steady state was achieved for both ct-HTBZ and f3-HTBZ at day 7 after a daily dose of 50 mg controlled-release tetrabenazine tablets for seven days. Dose accumulation was observed by comparing day 1 and day 7 Cmax and AUC data. The a-HTBZ and f3-HTBZ absorption (Cmax and AUC) calculated from the blood samples collected after the last dose on day 7 was much higher than that on day 1.

Comparative Example 1 Tetrabenazine so lubility The following example employs immediate-release tablets of tetrabenazine, in contrast to the controlled-release tablets of the present invention, to determine the solubility of tetrabenazine across the pH range 2-12.

The dissolution of tetrabenazine 12.5 mg and 25 mg immediate-release tablets was conducted in 0.1 M hydrochloric acid solution (pH 1.5).

The so lubility of tetrabenazine was determined across the pH range 2-12 in water, adjusted with hydrochloric acid/sodium hydroxide as necessary and if feasible complete dissolutions at pH 7.0 and pH 12.

It was found that tetrabenazine was soluble in pH 2 hydrochloric acid solution at approximately 850.0 mg/100 ml (i.e. 1 in 117 -categorised as slightly soluble).

The solubility decreased significantly between pH 2 and pH 3, such that at pH 3 it was only soluble at approximately 4.0 mg/100 ml (i.e. 1 in 25,000 -categorised as practically insoluble). The solubility remained relatively constant between pH 4 and pH 12 at approximately 3.0 mg/100 ml (i.e. 1 in 33,333 -categorised as practically insoluble).

It was not feasible to complete tablet dissolution at pH 7 and pH 12 because of the lack of solubility.

All samples were protected from light throughout the experiment.

In summary, tetrabenazine was found to be practically insoluble at the pH range of 3- 12 and slightly soluble at approximately 850 mg/100 ml at pH 2 (i.e. 1 in approximately 117).

Claims

CLAIMS1. A controlled release pharmaceutical composition in a unit dosage form comprising tetrabenazine as the sole therapeutic agent and a release-retarding agent.
2. The pharmaceutical composition according to claim 1, wherein the solid dosageform is a tablet.
3. The pharmaceutical composition according to claim 2, wherein the tablet comprises tetrabenazine dispersed in a matrix of release-retarding agent.
4. The pharmaceutical composition according to any preceding claim, wherein the release-retarding agent is a cellulose derivative.
5. The pharmaceutical composition according to claim 4, wherein the cellulose derivative is hydroxypropylmethyl cellulose (HPMC).
6. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 10-110 mg of tetrabenazine as the sole therapeutic agent.
7. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 15-100 mg of tetrabenazine as the sole therapeutic agent.
8. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 20-90 mg of tetrabenazine as the sole therapeutic agent.
9. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 25-80 mg of tetrabenazine as the sole therapeutic agent.
10. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 30-70 mg of tetrabenazine as the sole therapeutic agent.
11. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 35-65 mg of tetrabenazine as the sole therapeutic agent.
12. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 40-60 mg of tetrabenazine as the sole therapeutic agent.
13. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 50 mg of tetrabenazine as the sole therapeutic agent.
14. The pharmaceutical composition according to any preceding claim, wherein the unit dosage form comprises 25 mg of tetrabenazine as the sole therapeutic agent.
15. The pharmaceutical composition according to any preceding claim, wherein tetrabenazine comprises 4-40% (w/w) of the composition.
16. The pharmaceutical composition according to any preceding claim, wherein tetrabenazine comprises 10-30% (w/w) of the composition.
17. The pharmaceutical composition according to any preceding claim, wherein tetrabenazine comprises 15-25% (w/w) of the composition.
18. The pharmaceutical composition according to any preceding claim, wherein the release-retarding agent comprises 20-40% (w/w) of the composition.
19. The pharmaceutical composition according to any preceding claim, wherein the composition comprises further pharmaceutical excipients including at least one of a diluent, disintegrant, glidant and lubricant.
20. The pharmaceutical composition according to claim 19, wherein the diluent is a sugar.
21. The pharmaceutical composition according to claim 20, wherein the sugar is lactose.
22. The pharmaceutical composition according to claims 19-2 1, wherein the disintegrant is starch.
23. The pharmaceutical composition according to claims 19-22, wherein the glidant is talc and/or colloidal silicon dioxide.
24. The pharmaceutical composition according to claims 19-23, wherein the lubricant is magnesium stearate.
25. The pharmaceutical composition according to claims 19-24, wherein the diluent comprises 35-45% (w/w) of the composition.
26. The pharmaceutical composition according to claims 19-25, wherein the disintegrant comprises 15-25% (w/w) of the composition.
27. The pharmaceutical composition according to claims 19-26, wherein the glidant comprises 2-8% (w/w) of the composition.
28. The pharmaceutical composition according to claims 19-27, wherein the lubricant comprises 1-2% (w/w) of the composition.
29. A pharmaceutical composition in the form of a tablet comprising tetrabenazine as the sole therapeutic agent in an amount of between 40-60 mg, and the composition further comprising lactose, starch, HPMC, talc and magnesium stearate.
30. A pharmaceutical composition as defined in any preceding claim for use in therapy.
31. A process for the preparation of the pharmaceutical composition according to any preceding claim, wherein the composition is prepared by mixing tetrabenazine and the release-retarding agent and optionally other excipients to form granules and compressing the granules to form a tablet.